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PubMed2004

Influence of genetic polymorphisms of the renin-angiotensin system on IgA nephropathy.

BACKGROUND: We evaluated the impact of the three major genetic polymorphisms of the renin-angiotensin system [angiotensinogen (AGT) gene M235T, angiotensin-converting enzyme (ACE) gene-I/D and angiotensin II-type 1 receptor (AT1R) gene A1166C polymorphisms] as risk factors in IgA nephropathy. METHODS: The clinical course of 107 patients with biopsy proven IgA nephropathy followed up for 6.6 +/- 5.8 years was examined. The genetic polymorphisms were determined by PCR amplification. RESULTS: The allele frequencies of the polymorphisms studied were similar in patients and control subjects. AGT-M235T genotype was associated with the presence of nephrotic syndrome (p < 0.05), correlated to the number of antihypertensive drugs agents taken (p < 0.01) and influenced the rate of deterioration of renal function (p < 0.05). Combined analysis of AGT-M235T and ACE-I/D polymorphisms detected an interaction on affecting progression (p < 0.05). ACE-inhibition had a more pronounced effect in certain AGT-M235T and ACE-I/D genotypes (p < 0.05) and their combined analysis showed a synergistic effect (p < 0.01). No association between AT(1)R-A1166C polymorphism and any of the parameters studied was observed. CONCLUSIONS: Our results suggest that angiotensinogen-M235T polymorphism is an important marker of progression in IgA nephropathy in Caucasian patients, especially when analyzed in combination with ACE-I/D polymorphism.

Female↗

PubMed2004

ADRB2 polymorphisms and asthma susceptibility: transmission disequilibrium test and meta-analysis.

BACKGROUND: The beta(2)-adrenergic receptor (ADRB2) is the most common adrenergic receptor in the lung, and associations between ADRB2 polymorphisms and intermediate phenotypes of asthma have been reported. Four missense polymorphisms (Arg16Gly, Gln27Glu, Val34Met, and Thr164Ile) and one polymorphism in the 5' leader cistron of the ADRB2 messenger RNA has been identified. In vitro studies have shown that these missense polymorphisms can affect ADRB2 function. METHODS: To examine possible associations of ADRB2 polymorphisms with asthma susceptibility, we performed transmission disequilibrium tests (TDT) of 137 Japanese families identified through children with atopic asthma. RESULTS: We did not find associations between any alleles of the ADRB2 polymorphisms and asthma by TDT (p > 0.1). We also performed a meta-analysis of data from all available studies. The random-effects model showed no significant odds ratio for the Arg16Gln (odds ratio = 1.05, p = 0.53) or Gln27Glu (odds ratio = 1.12, p = 0.22) polymorphism. CONCLUSION: Our data indicate that ADRB2 does not contribute substantially to susceptibility to asthma, but it is possible that these polymorphisms influence disease activity and drug responses in individuals with asthma.

Adolescent↗

PubMed2006

Association of the -1438G/A polymorphism of the 5-HT2A receptor gene with obstructive sleep apnea syndrome.

OBJECTIVE: Serotonergic neurons innervating motoneurons increase their firing rates in response to respiratory challenges, and long-term facilitation of respiratory activity in response to hypoxia is serotonin (5-HT) dependent. Polymorphism of the genes which code for 5-HT receptors may affect functions of the serotonergic system, and may be associated with obstructive sleep apnea syndrome (OSAS). The objective in this study was to assess the significance of T102C and -1438G/A polymorphisms of the 5-HT2A receptor gene in OSAS. METHODS: Fifty-five patients with OSAS and 102 healthy volun teers were included for genetic analyses of T102C and -1438G/A polymorphisms of the 5-HT2A receptor gene. RESULTS: For the T102C polymorphism, there was no significant difference between the patients and controls and both genders (p > 0.05). For the -1438G/A polymorphism, the A/A and G/A genotypes were overrepresented in the patients and controls, respectively (p = 0.045). In the control group, the genotypes of both genders were not significantly different (p > 0.05). In the patients, the A/A and G/A genotypes were overrepresented in males and females, respectively (p = 0.035). Concerning males, the A/A genotype was overrepresented in patients (p = 0.007). CONCLUSION: Serotonergic mechanisms appear to be related to OSAS. The T102C polymorphism of the 5-HT2A receptor gene is not associated with OSAS. However, the -1438G/A polymorphism is associated with OSAS occurrence, especially in male patients. This polymorphism may also be associated with different OSAS incidences of both genders.

Case-Control Studies↗

PubMed2006

Impact of methionine synthase gene and methylenetetrahydrofolate reductase gene polymorphisms on the risk of sudden sensorineural hearing loss.

Idiopathic sudden sensorineural hearing loss (SSNHL) represents a frequently encountered otological disease of unknown etiology. In recent years, several inherited risk factors have been found in the pathogenesis of vascular diseases. In the present study, we determined whether specific polymorphism or the combination of polymorphisms in folate-dependent homocysteine metabolism genes can act as predisposing inherited vascular risk factors in the development of SSNHL. We conducted a prospective case-control study using DNA samples extracted from 81 patients diagnosed as suffering from SSNHL and 264 healthy control subjects. Three functional polymorphisms were analyzed by polymerase chain reaction amplification, restriction enzyme digestion, and DNA fragment separation by electrophoresis: methylenetetrahydrofolate reductase (MTHFR) C677T, MTHFR A1298C, and methionine synthase (MTR) A2756G polymorphisms. The prevalence of the homozygous genotype of MTR 2756GG in the SSNHL patients (9%) was significantly higher than in the control group (4%) (p = 0.011). The allelic frequency of the G allele of the MTR A2756G polymorphism among SSNHL patients (12.5%) was also significantly higher than in the control group (5%) (p = 0.033). The prevalence of patients possessing two polymorphisms (31%) and three polymorphisms (17%) in the SSNHL group was significantly higher than in the control group (23 and 9%, respectively; p = 0.019). The frequency of patients with a very high rank risk (double homozygous) was significantly higher in the SSNHL group, MTHFR 677TT/MTR 2675GG--7%, than the frequency of patients in the control group, MTHFR 677TT/MTR 2675GG--3% (p = 0.030). Certain polymorphisms in genes encoding enzymes in the folate-dependent homocysteine metabolism are associated with SSNHL. In our case-control study, a significant association between MTR 2756GG genotype and SSNHL was found which may represent an inherited vascular risk factor in the pathogenesis of SSNHL.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗

PubMedDate not supplied

Analysis of factor VIII gene polymorphisms in Brazilian blacks reveals further differences in the black population.

We report here the analysis of four intragenic (BclI, HindIII, XbaI, and BglI) and two extragenic (MspI and TaqI/St14) polymorphisms associated with the factor VIII gene in the Brazilian Black population. No difference was observed for the allelic frequencies of the BclI, HindIII, and BglI polymorphisms when we compared our results with those reported for North American Blacks. For the first time, the XbaI and MspI polymorphisms were investigated in a Black population. Interestingly, the XbaI polymorphism is almost monomorphic for the Brazilian Black population, differing in this respect from all other populations studied thus far. The MspI polymorphism presents inverse allelic frequencies for the Brazilian Blacks when compared with Caucasians, as observed for the BclI and HindIII polymorphisms. Analysis of the TaqI/St14 multiallelic system revealed five novel alleles (ranging from 5.8 to 11.0 kb) which may represent unique alleles for the Black population. The results show that analysis of factor VIII gene polymorphisms and haplotypes may be successfully used for investigating interrelationships between human populations. The results also allow definition of a strategy for carrier detection and prenatal diagnosis of hemophilia A in this population based on analysis of factor VIII gene polymorphisms, which is considered an alternative approach for those families where identification of gene mutation is not feasible.

Alleles↗

PubMed1992

DNA polymorphism in the beta-globin gene cluster in Saudi Arabs: relation to severity of sickle cell anaemia.

Significant DNA polymorphisms have been reported in the beta-globin gene cluster of epsilon-G gamma-A gamma-psi beta-delta-beta-gene region, in normal (Hb AA) individuals and in patients with sickle cell anaemia (SCA). Investigations of the extent of the DNA polymorphisms in the beta A- and beta S-globin gene cluster using Hind III, Hinc II, Ava II, Xmn I, and Hpa I, revealed several associations with mild SCA. The correlation of the presence (+) or absence (-) of the restriction endonuclease site to clinical severity in patients homozygous for beta S-gene showed that the mild form of SCA was associated mainly (> 90%) with the Xmn I polymorphic site 5' to G gamma, and to a lesser extent with Hinc II polymorphic site 5' to epsilon and in the psi beta-gene, with Hind III polymorphic site in G gamma and Hpa I polymorphic site 3' to the beta-globin gene, while in the severe form of SCA these polymorphic sites were absent in most patients. The polymorphism in the beta-globin gene cluster was significantly related to the expression of the beta S-gene and clinical severity of SCA.

Anemia, Sickle Cell↗

PubMed2006

Polymorphism in endothelin-related genes limits exercise-induced decreases in arterial stiffness in older subjects.

Increase in arterial stiffness is associated with aging, which is improved by regular exercise. Endothelin (ET) system has crucial roles in regulating vascular tone and in the progression of atherosclerosis. We hypothesized that molecular variations (ie, gene polymorphisms) in ET-related gene might affect exercise-induced improvement in arterial stiffness with age in human subjects. The present study provides a cross-sectional investigation of 191 healthy middle-aged and older (65+/-1 years) human subjects to clarify the relationship between the regular exercise-induced improvement of arterial stiffness and the gene polymorphisms of ET converting enzyme (ECE)-1, ECE-2, ET-A receptor (ET-A), and ET-B receptor (ET-B). The study subjects were divided into active and inactive groups based on the median value (186 kcal/d) of energy expenditure. Brachial-ankle arterial pulse wave velocity (baPWV) was used to evaluate arterial stiffness. All individuals were genotyped for 4 different polymorphisms of the ET system: 2013(+289)A/G in intron 17 of ECE-1, 669(+17)T/C in intron 5 of ECE-2, 958A/G in exon 6 of ET-A, and 831A/G in exon 4 of ET-B. The baseline baPWV was significantly lower in the active group without any change in blood pressure. Polymorphisms in ECE-1 influenced basal blood pressure. Polymorphisms in ECE-1 and ECE-2 had no effect on baPWV between active and inactive groups. However, polymorphisms in both ET-A and ET-B affected baPWV in the 2 groups. The present results suggest that differences in ET-A and ET-B polymorphisms may influence the response of the vascular wall to exercise whereas ECE-1 polymorphisms may affect basal blood pressure.

Aged↗

PubMed2003

The promoter polymorphism in the eosinophil cationic protein gene and its influence on the serum eosinophil cationic protein level.

Asthma is characterized by reversible airway obstruction and airway inflammation. Serum levels of eosinophil cationic protein (ECP) might reflect eosinophilic airway inflammation and asthma activity. However, serum ECP levels are not elevated in some patients with asthma, even when they are symptomatic. In this study, we screened for polymorphisms in the ECP gene and analyzed association between these polymorphisms and asthma and serum ECP levels in 137 Japanese families identified through children with asthma. We identified three polymorphisms (-393C/T, -38C/A, and 124Arg/Thr) in human ECP. We did not find associations between these polymorphisms and asthma by the transmission disequilibrium test. However, we found that serum ECP levels in subjects with the -393T allele were significantly lower than those in subjects with the -393C allele. A reporter construct with the -393T allele showed significantly lower promoter activity than one with the -393C allele. Gel shift assay revealed that C/EBP proteins can bind the -393C/T polymorphic site. These data indicate that C/EBP proteins play an important role in the regulation of ECP and that a significant amount of the variance in baseline serum ECP levels may be explained by the -393C/T polymorphism. Although ECP polymorphisms are not likely to be involved in the development of asthma, measurement of ECP levels for the assessment of asthma activity may be improved when done in combination with genotyping of the -393C/T polymorphism.

Adolescent↗

PubMed2001

Role of 4 platelet membrane glycoprotein polymorphisms on experimental arterial thrombus formation in men.

This study investigates whether the polymorphisms of 3 important platelet receptors affected experimental thrombus formation in men. Forty healthy male volunteers randomly recruited were genotyped for the variable number of tandem repeat (VNTR) of GPIbalpha, the -5T/C polymorphism in the Kozak sequence of GPIbalpha, the 807C/T polymorphism of GPIa, and the PI(A1)/PI(A2) polymorphism of GPIIb/IIIa. Platelet thrombus formation was induced ex vivo by exposing a collagen-coated coverslip in a parallel plate perfusion chamber to native blood for 4 minutes. The shear rates at the collagen surface were 650 and 2600 x s(-1). At 2600 x s(-1) platelet thrombus formation was significantly related only to the 807C/T polymorphism. In contrast, at 650 x s(-1) thrombus formation was significantly altered only by the Kozak sequence polymorphism. The VNTR and the PI(A1)/PI(A2) polymorphisms did not influence thrombus formation. Thus, platelet thrombus formation is significantly influenced by genetic variations of the GPIbalpha and GPIa receptors. The effect of these polymorphisms was dependent on the blood flow rate.

Adult↗

PubMed2006

Genetic polymorphisms of MMP1, MMP3 and MMP7 gene promoter and risk of colorectal adenoma.

BACKGROUND: Matrix metalloproteinases (MMP) have been shown to play a role in colorectal cancer (CRC). More recently, MMP1, MMP3 and MMP7 functional gene promoter polymorphisms have been found to be associated with CRC occurrence and prognosis. To document the role of MMP polymorphisms in the early step of colorectal carcinogenesis, we investigated their association with colorectal adenoma risk in a case-control study comprising 295 patients with large adenomas (LA), 302 patients with small adenomas (SA) and 568 polyp-free (PF) controls. METHODS: Patients were genotyped using automated fragment analysis for MMP1 -1607 ins/del G and MMP3 -1612 ins/delA (MMP3.1) polymorphisms and allelic discrimination assay for MMP3 -709 A/G (MMP3.2) and MMP7 -181 A/G polymorphisms. Association between MMP genotypes and colorectal adenomas was first tested for each polymorphism separately and then for combined genotypes using the combination test. Adjustment on relevant variables and estimation of odds ratios were performed using unconditional logistic regression. RESULTS: No association was observed between the polymorphisms and LA when compared to PF or SA. When comparing SA to PF controls, analysis revealed a significant association between MMP3 -1612 ins/delA polymorphism and SA with an increased risk associated with the 6A/6A genotype (OR = 1.67, 95% CI: 1.20-2.34). Using the combination test, the best association was found for MMP3.1-MMP1 (p = 0.001) with an OR of 1.88 (95% CI: 1.08-3.28) for the combined genotype 2G/2G-6A/6A estimated by logistic regression. CONCLUSION: These data show a relation between MMP1 -1607 ins/del G and MMP3 -1612 ins/delA combined polymorphisms and risk of SA, suggesting their potential role in the early steps of colorectal carcinogenesis.

Adenomatous Polyps↗

PubMed2006

Lack of association between putative transporter gene polymorphisms in Plasmodium falciparum and chloroquine resistance in imported malaria isolates from Africa.

BACKGROUND: Plasmodium falciparum drug resistance represents a major health problem in malaria endemic countries. The mechanisms of resistance are not fully elucidated. Recently, an association between putative transporter gene polymorphisms and in vitro response to chloroquine (CQ) and quinine has been reported in culture-adapted, cloned isolates from various geographical origins. However, this was not confirmed in another study performed on isolates from a defined region in Thailand. METHODS: This study tried to find an association between putative transporters gene polymorphisms with in vitro response to CQ and pfcrt genotype in isolates originating from various African countries. To avoid biases of parasites adaptation in culture, fresh isolates obtained from symptomatic, malaria-infected travellers returning from Africa to France were used. Monoclonal isolates included in the study were selected using a msp-2 fragment analysis method. In vitro susceptibility to CQ, single nucleotide polymorphisms and microsatellite polymorphisms in pfcrt, pfmdr1 and six putative transporter genes were established in 27 isolates and three reference strains. RESULTS: Polymorphism of pfcrt at positions 76 and 220 showed a significant association with in vitro chloroquine resistance (P < .02 and P < .05 respectively). Polymorphism of pfmdr1 at position 86 showed an equally significant association with in vitro chloroquine response (P < .05). No association was found between SNPs or microsatellite polymorphisms of putative transporter genes and in vitro CQR or pfcrt genotype in imported malaria isolates from Africa. CONCLUSION: The previously described association between putative transporter gene polymorphisms and in vitro response to chloroquine (CQ) was not confirmed in the present study.

Africa↗

PubMed2004

Role of tumour necrosis factor gene polymorphisms (-308 and -238) in breast cancer susceptibility and severity.

INTRODUCTION: Genetic polymorphisms in the promoter region of the tumour necrosis factor (TNF) gene can regulate gene expression and have been associated with inflammatory and malignant conditions. We have investigated two polymorphisms in the promoter of the TNF gene (-308 G>A and -238 G>A) for their role in breast cancer susceptibility and severity by means of an allelic association study. METHODS: Using a case-control study design, breast cancer patients (n = 709) and appropriate age-matched and sex-matched controls obtained from the Breast Screening Unit (n = 498) were genotyped for these TNF polymorphisms, using a high-throughput allelic discrimination method. RESULTS: Allele frequencies for both polymorphisms were similar in both breast cancer cases and controls. However, the -308 polymorphism was found to be associated with vascular invasion in breast tumours (P = 0.024). Comparison with other standard prognostic indices did not show any association for either genotype. CONCLUSIONS: We demonstrated no association between the -308G>A polymorphism and the -238G>A polymorphism in the promoter region of TNF and susceptibility to breast cancer, in a large North European population. However, the -308 G>A polymorphism was found to be associated with the presence of vascular invasion in breast tumours.

Adult↗

PubMed2004

Polymorphisms in the fatty acid-binding protein 2 and apolipoprotein C-III genes are associated with the metabolic syndrome and dyslipidemia in a South Indian population.

The Chennai Urban Population Study investigates a South Indian population with a high prevalence of cardiovascular disease associated with the metabolic syndrome (MS). The Ala54Thr polymorphism in the fatty acid-binding protein 2 (FABP2) gene as well as the T-455C and C-482T polymorphisms in the apolipoprotein C-III (APOC3) gene promoter have been associated with features of the MS in specific populations. This study evaluates in Asian-Indians the association between these polymorphisms with MS and dyslipidemia, defined according to National Cholesterol Education Program Adult Treatment Panel III. Allelic frequencies in 70 controls and 110 patients with diabetes from the Chennai Urban Population Study were 52.9% for FABP2 Thr54, 73.0% for APOC3 -482T, and 80.2% for APOC3 -455C. The polymorphisms were in agreement with Hardy-Weinberg equilibrium. Controls carrying FABP2 Thr54 were more likely to have MS than noncarriers (Fisher's exact test P = 0.031; odds ratio = 6.9 with a 95% confidence interval of 1.1, 43.9). Those carrying at least one polymorphic allele in both genes had a higher likelihood of having MS than wild type (Fisher's exact test P = 0.003; odds ratio = 12.1 with a 95% confidence interval of 1.88, 77.6). Dyslipidemia was associated with the polymorphism as well. The polymorphisms were not associated with MS in patients with diabetes. The association of the polymorphisms with MS and dyslipidemia could contribute to the high cardiovascular disease prevalence in this population.

Adult↗

PubMed2006

Common polymorphisms of the growth hormone (GH) receptor do not correlate with the growth response to exogenous recombinant human GH in GH-deficient children.

CONTEXT: GH acts through the GH receptor (GHR), whose polymorphisms might affect the growth response to recombinant human GH (rhGH). OBJECTIVE: The objective of this study was to investigate possible influences of GHR polymorphisms on the growth response to rhGH in GH-deficient (GHD) children. DESIGN: This was a 2-yr study (first year, spontaneous growth; second year, growth during rhGH treatment). SETTING: This study was performed at a referral center. PATIENTS: Fifty-four prepubertal GHD children (11 females; mean age, 7.8 yr; sd, 3.96) were studied. INTERVENTION: Patients were treated with rhGH (0.2 mg/kg.wk) for at least 1 yr after diagnosis. Growth velocity (GV) was measured 1 yr before treatment and during the first treatment year. GHR exons were amplified by PCR using pairs of intronic primers. The presence of single or multiple mismatches in the PCR products was revealed by denaturing high-pressure liquid chromatography. For exons in which mismatches were found by denaturing high-pressure liquid chromatography, direct sequencing was performed by automatic sequencer. MAIN OUTCOME MEASURES: Before the start of treatment, the mean height (Ht) sd score was -1.93 (sd, 0.70), and the mean GV sd score was -1.49 (sd, 1.26). RESULTS: The posttreatment (first 12 months) mean GV sd score was 3.55 (sd, 3.27). Molecular analysis revealed a high frequency of GHR polymorphisms; in particular: exon 3 deletion (Del 3) in 26 subjects (48%), polymorphism 504 A>G at codon 168 of exon 6 in 44 (82%), and polymorphism 1576 A>C at codon 526 of exon 10 in 35 (65%). In most patients, these different polymorphisms recurred in association. We found no significant differences in GV between the groups of subjects defined by the polymorphic genotypes. CONCLUSION: The most common GHR polymorphisms, alone or in association, do not appear to affect the growth response to rhGH in GHD children.

Child↗

PubMed2002

Contribution of APOE promoter polymorphisms to Alzheimer's disease risk.

OBJECTIVE: To determine whether the effects of APOE promoter polymorphisms on AD are independent of the APOE-epsilon4 allele. BACKGROUND: Recently, the -491 A-->T and -219 G-->T polymorphisms located in the APOE promoter have been suggested to be risk factors for AD. However, the effects of these polymorphisms have not always been reproduced in case-control studies, possibly because of the strong linkage disequilibrium existing at this locus or the characteristics of the populations studied. METHODS: Data collection was performed from six independent samples (1,732 patients with AD and 1,926 control subjects) genotyped for APOE exon 4 and the two APOE promoter polymorphisms. The risks associated with the APOE polymorphisms for developing AD were estimated using logistic regression procedures and calculation of odds ratios with 95% CI adjusted by age, sex, and collection center. Independence of the APOE promoter polymorphisms was tested by stratification for APOE-epsilon4 and tertile design was used for age stratification. RESULTS: The independence of the -491 AA genotype was observed in the whole sample whereas the independence of the -219 TT genotype was observed only in the oldest population. CONCLUSION: The -491 and -219 APOE promoter polymorphisms incur risk for AD in addition to risk associated with the APOE-epsilon4 allele, with age accentuating the effect of the -219 TT genotype. Because these polymorphisms appear to influence apoE levels, these results suggest that APOE expression is an important determinant of AD pathogenesis.

Aged↗

PubMed2004

Evaluation of the Lys198Asn and -134delA genetic polymorphisms of the endothelin-1 gene.

Endothelin-1 (ET-1) is a potent vasoconstrictor and shows various pharmacological responses. Two single nucleotide polymorphisms in the ET-1 gene (EDN1) have been reported to be associated with blood pressure (BP). One is the Lys198Asn polymorphism, which showed a positive association with BP in overweight people. Another is the 3A/4A polymorphism (-134delA) located in the 5'-untranslated region. In this study, we investigated the expression of the Lys198Asn polymorphism in ET-1 in vitro, as well as the association between either of the two polymorphisms and the plasma ET-1 level. We expressed both the major (Lys-type) and minor type (Asn-type) preproET-1 in three different cell lines, and measured the levels of ET-1 and big ET-1 in the culture supernatant. There was no significant difference in the levels of ET-1 or big ET-1 between the Asn-type and Lys-type transfectant. In the association study, the plasma levels of ET-1 in 54 hypertensive patients having an amino acid substitution from Lys to Asn at position 198 were not different from those of hypertensives without the substitution. However, we found a significant difference in ET-1 levels between individuals with the 3A/3A and 3A/4A genotypes. Our transient expression study indicates that the Lys198Asn polymorphism may not directly affect ET-1 and big ET-1 production. Another variant in the EDN1 gene in linkage disequilibrium with the Lys198Asn polymorphism may be responsible for the association with BP, or the interaction between the EDN1 Lys198Asn polymorphism and other factors such as obesity may be involved in the mechanisms elevating BP in vivo.

5' Untranslated Regions↗

PubMed2005

Vitamin D receptor Fok1 polymorphisms affect calcium absorption, kinetics, and bone mineralization rates during puberty.

UNLABELLED: Few studies of the VDR polymorphisms have looked at calcium metabolism or long-term effects. We measured bone mineralization and calcium metabolic parameters longitudinally in a group of 99 adolescents. We found a significant relationship between calcium absorption and skeletal calcium accretion and the Fok1, but not other VDR or related, genetic polymorphisms. It seems that the Fok1 polymorphism directly affects bone mineralization during pubertal growth through an effect on calcium absorption. INTRODUCTION: There are few data regarding the relationship between genetic markers for low bone mass and changes in calcium metabolism in childhood or adolescence. We sought to identify the effects of polymorphisms of the vitamin D receptor (VDR) on calcium and bone mineral metabolism in a longitudinal study of pubertal adolescents. MATERIALS AND METHODS: Adolescents (n = 99) received comprehensive stable isotope studies of calcium absorption, bone calcium kinetics, and bone mineralization. Studies were repeated 12 months later. Polymorphisms of putative genetic markers were determined and related to bone mineralization and calcium metabolic finding. Results were analyzed by ANOVA in which changes over time were determined using the initial value as a covariate. RESULTS: Polymorphisms of the Fok1 gene of the VDR were significantly related to calcium absorption (p = 0.008) and whole body BMC (p = 0.03) and BMD (p = 0.006). The Fok1 effect on whole body BMD was significant for those with Ca intake >800 mg/day (p < 0.001), whereas for those with Ca intake < or = 800 mg/day, the Fok1 genotype did not have a significant effect on whole body BMD (p = 0.40). The Fok1 genotype was significantly related to the changes during the year in whole body calcium accretion, with the ff genotype having a 63 +/- 20 mg/day deficit compared with the FF genotype (p = 0.008). CONCLUSIONS: The Fok1 polymorphism of the VDR receptor seems to directly affect bone mineral accretion during pubertal growth through an effect on calcium absorption. The relationship between different genetic polymorphisms and bone mineral metabolism may vary by life stage as well as diet.

Analysis of Variance↗

PubMed2005

Polymorphisms in the aromatase gene predict areal BMD as a result of affected cortical bone size: the GOOD study.

UNLABELLED: The association between aromatase gene polymorphisms, bone parameters, and sex steroid levels was studied in 1068 men (18.9 +/- 0.6 years of age). Several aromatase gene polymorphisms were found to be associated with serum testosterone levels and cortical bone size but not with trabecular volumetric BMD. INTRODUCTION: Both testosterone and estrogens are important for the male skeleton. Aromatase, the product of the CYP19 gene, is the key enzyme in the conversion of testosterone to estradiol. A functional aromatase enzyme has been shown to be crucial for the normal development of the male skeleton. The role of genetic polymorphisms in the aromatase gene for trabecular volumetric BMD (vBMD) and cortical bone size has not previously been studied in men. MATERIALS AND METHODS: The Gothenburg Osteoporosis and Obesity Determinants (GOOD) study consists of 1068 men (18.9 +/- 0.6 years of age). The TTTA repeat polymorphism (TTTAn) and three single nucleotide polymorphisms (SNPs), including the Val80 SNP, in the CYP19 gene, were analyzed. Serum levels of testosterone and estradiol were measured. Areal BMD (aBMD) was measured by DXA, whereas cortical and trabecular vBMD and cortical bone size were measured by pQCT. RESULTS: The TTTAn and the Val80 genotypes were independent predictors of aBMD of the radius, lumbar spine, total body, and cortical bone size (cortical cross-sectional area and thickness) of both the radius and tibia. In contrast, trabecular vBMD was not associated with CYP19 polymorphisms. Homozygosity for the long allele (>9 repeats) of the TTTAn and for the G allele of the Val80 SNP was associated with the highest aBMD and testosterone levels as well as with the greatest cortical bone size. Regression analyses indicated that the association with aBMD was mediated through affected cortical bone size. CONCLUSIONS: We showed, in a large well-characterized cohort of men at the age of peak bone mass, that several common aromatase polymorphisms are associated with cortical bone size but not with trabecular vBMD. One may speculate that affected CYP19 activity, resulting in altered testosterone levels during pubertal development, might contribute to the association between CYP19 polymorphisms and cortical bone size.

Absorptiometry, Photon↗